An individual who is exposed to HIV-1 contaminated blood or other bodily fluids runs a significant risk of becoming infected with the virus. The goal of post-exposure prophylaxis is to protect exposed individuals from an anticipated infection. The major clinical settings for HIV-1 post- exposure prophylactic therapy include: occupational transmission as a result of accidental needle-stick injuries sustained by health care workers, and vertical transmission from an infected pregnant woman to her newborn child. In this regard, passive transfer of human immunoglobulins to an exposed individual has been successfully used to prevent or treat many viral infections of man. In this Phase I project, we will develop a recombinant CD4-immunoglobulin protein, termed CD4-IgG2, as a novel post-exposure prophylactic agent against HIV-1. CD4-IgG2 is a heterotetramer containing two chains of a CD4-human IgG2 heavy chain fusion protein and two chains of a CD4-human kappa light chain fusion protein. The major advantage of CD4-IgG2 is that CD4-based molecules can neutralize all strains of HIV-1, including primary isolates of the virus. We will perform in vitro experiments to determine the ability of CD4-IgG2 to neutralize a large panel of primary isolates of HIV-1, including strains with different tropisms as well as strains isolated from different stages of the disease and from different clades of the virus. Ex vivo neutralization experiments will also be performed using viremic plasma from HIV-1-infected individuals. In addition to CD4- IgG2, several neutralizing monoclonal antibodies against HIV-1 will be included in these experiments for comparative analysis of the different agents. Finally, we will perform initial HIV-1 protection experiments in hu-PBL-SCID mice (mice with severe combined immunodeficiency transplanted with normal human peripheral blood leukocytes) to test the in vivo antiviral activity of CD4-IgG2. The hu-PBL-SCID mouse is a suitable model for evaluation of potential agents for prophylaxis HIV-1. The development of a safe and effective post-exposure prophylactic agent against HIV-1 is an urgent public health priority. The overall goal of this Phase I project is to determine the suitability of CD4-IgG2 for further development as an immunoprophylactic agent. PROPOSED COMMERCIAL APPLICATION: Development of a CD4-immunoglobulin protein as a post-exposure prophylactic agent against HIV-1.